
Uptravi (Selexipag) Assessment Report
rat repeated-dose toxicity studies (e.g. for treprostinil). Haemorrhage in the alveoli of lungs at doses of
> 20 mg/kg/day selexipag might be explained by the platelet-inhibitory effects of selexipag.
Dogs were the more sensitive species compared to rats in repeated dose toxicity studies performed
with selexipag. In juvenile dogs, the major clinical findings were related to selexipag-induced
disturbance of intestinal motility leading to the development of intussusception with changes in stool,
prolapse of anus and dark red discoloration in the jejunum and intussusception (jejunum), which
manifested histologically as haemorrhagic infarction (necrosis, haemorrhage and congestion of the
intestinal mucosa; at doses of > 2 mg/kg/day). Intussusception was the cause of death (3 animals at a
dose of 20 mg/kg/day in the 14 day study, 2 animals at a dose of 4 mg/kg/day in the 39 week study).
The mechanism for the development of gastrointestinal alterations induced in dogs by selexipag has
been discussed by the Applicant. In contrast to other prostaglandins, prostacyclin (PGI2) prevents
diarrhoea caused by other prostaglandins, PGI2 inhibits gastric acid secretion and is cytoprotective for
the stomach and the small intestine, and the antidiarrheal activity of PGI2 may be due to its
antipropulsive effects (Ruwart and Rush 1984). Administration of the prostacyclin analogue taprostene
induced hypermotility of the gastrointestinal tract resulting in intestinal invagination (intussusception)
in dogs (Wöhrmann et al. 1994). Intussusception is defined as prolapse of a proximal bowel segment
into a distal segment and may result in luminal obstruction, mucosal congestion or infarction.
Intussusception is more common in young dogs (< 6-8 month old; Merck Veterinary Manual), which is
the age of affected dogs in repeated dose toxicity studies performed with selexipag. Intussusception is
the most important cause of gastrointestinal obstruction in dogs (Mutasa et al. 1994). In humans,
intussusception is rare in adults and mainly observed in association with cancer, but it is relatively
common in children (Azar and Berger 1997, Duijff et al. 2007). The Applicant suggests that
intussusception is a result of exaggerated pharmacodynamics of selexipag in dogs. The risk for humans
to develop intussusception is considered low by the Applicant in view of the particular sensitivity of
dogs to IP receptor agonist-induced effects on intestinal motility, the increased sensitivity of young
dogs to develop intussusception and the safety margins for a human dose of 1600 µg b.i.d. According
to the Applicant, no case of intestinal invagination was reported during the clinical studies with
selexipag.
Intussusception did not occur in mouse or rat toxicity studies. However, in our view, safety margins at
the NOEL of 1 mg/kg/day regarding the gastrointestinal findings in dogs as obtained in the 39 week
study, corrected for species difference in receptor potency, are very low with values of 0.1 for
selexipag and 1 - 1.6 for ACT-333679, respectively, in relation to human exposure at a dose of 1600
µg b.i.d.. Therefore, the possible induction of gastrointestinal disturbances denoting intestinal
intususception (manifested as ileus or obstruction) induced by selexipag has been included as an
important potential risk in the Risk Management Plan, and special caution is needed in the treatment of
children, since children (and also young dogs) are more susceptible than adults to the induction of
intussusception (Azar and Berger 1997, Duijff et al. 2007).
The second most marked effect aside from the gastrointestinal effects observed in repeated dose
toxicity studies in dogs performed with selexipag were bone and bone marrow alterations. These
consisted of increased ossification of the trabeculae and periosteum and bands of fibroblasts with
collagen fibres ("fibrosis") in the femur and sternum (at doses of > 6 mg/kg/day in the 14 day study,
> 3 mg/kg/day in the 4 weeks study and at all doses (> 1 mg/kg/day) in the 39 weeks study).
Furthermore, the amount of hematopoietic tissue in the bone marrow of the femur and sternum was
affected: it decreased at doses of > 6 mg/kg/day in the 14 day study and > 3 mg/kg/day in the 4
week study, but increased at all doses (> 1 mg/kg/day) in the 39 week study. Extramedullary
haematopoiesis in the spleen was observed at a dose of 6 mg/kg/day in the 4 week study. In the 39
week repeated dose toxicity study in dogs, a NOAEL could not be established for bone/bone marrow
findings. Increased bone mass was still observed after 4 weeks of recovery in the 4-week dog toxicity